Mobilization of tissue-resident lymphocytes during secondary infection

继发感染期间组织驻留淋巴细胞的动员

• 批准号: 10056391
• 负责人: Tessa Bergsbaken
• 金额: $ 22.92万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-25 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056391
• 关键词: Address; Area; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Complex; Data; Disease; Generations; Genes; Genetic Transcription; HIV; Heterogeneity; Homeostasis; Immune; Immune response; Immunity; Immunization; In Vitro; Infection; Integrins; Intestines; Invaded; Knowledge; Location; Lymphocyte; Lymphocyte Biology; Lymphocyte Subset; Mediating; Memory; Microbe; Mucous Membrane; Mycobacterium tuberculosis; Natural regeneration; Neuropeptides; Pasteurella pseudotuberculosis; Pathogenicity; Phenotype; Play; Population; Proliferating; Role; Secondary to; Signal Transduction; Site; Surface; T memory cell; T-Lymphocyte; Techniques; Tissues; Vaccination; Work; base; cell motility; design; enteric infection; experimental study; functional outcomes; human pathogen; improved; in vivo; innovation; insight; interest; migration; mucosal vaccine; pathogen; pathogenic bacteria; prevent; receptor; recruit; response; secondary infection; vaccination strategy; vaccine efficacy

T cells play a critical role in eliminating pathogens and the generation of memory T cells is an important component in protection from secondary infection. Memory T cells can be broadly divided into two groups based on their location, those that are capable of circulating throughout the body and those that are lodged in tissues, poised to respond rapidly to secondary infection. Tissue-resident memory T cells (Trm) cells remain in the tissue and are not replenished by circulating cells after infection is resolved. Circulating T cells are often not sufficient to protect from secondary infection; therefore, it is of significant interest to determine how to maximize the number and functionality of Trm cells as they are critical for robust tissue-specific immunity. Only a small number of microbes need to breach the mucosal surface to initiate disease; however, the mechanism by which established Trm populations detect and migrate to new areas of infection remains unexplored. Our earlier work, using the intestinal bacterial pathogen Yersinia pseudotuberculosis (Yptb), identified two distinct CD8+ Trm populations in the intestine that are differentiated by their expression of the integrin CD103. CD103neg Trm cells preferentially localize to lymphocyte clusters that form around areas of infection and limit pathogen replication, but dissipate after infection is resolved. CD103neg CD4+ and CD8+ Trm populations are also abundant in other tissues, but their respective roles in tissue-specific immunity remain poorly understood. We hypothesize the diversity in the tissue-resident lymphocyte population underlies a functional heterogeneity, with the CD103neg subset of lymphocytes capable of localized migration in response to tissue-specific signals that alert them to a pathogenic insult and forms the basis for lymphocyte cluster formation around new areas of infection during secondary challenge. These studies will utilize photoconversion to mark tissue-resident cells and allowing us to track cellular migration during homeostasis and intestinal infection. We will leverage this technique to address fundamental gaps in our knowledge of Trm biology including: (1) how Trm diversity relates to functional outcomes during secondary infection and (2) the identification of signals generated by the tissue in response to infection that drive Trm mobilization and pathogen control. These experiments have the potential to significantly advance our understanding of tissue-resident lymphocyte biology and how immunization strategies can be tailored to improve Trm functionality.

T细胞在消除病原体中起着关键作用，记忆T细胞的产生是一个重要的机制。 是防止继发感染的重要组成部分。记忆T细胞可以广泛地 根据位置分为两组，那些能够在整个 身体和那些留在组织中的，准备对继发感染迅速作出反应。 组织驻留记忆T细胞（Trm）细胞保留在组织中，并且不被补充。 感染后的循环细胞被解决。循环T细胞通常不足以保护 免受二次感染;因此，确定如何最大限度地提高感染率具有重要意义 Trm细胞的数量和功能，因为它们对于强大的组织特异性免疫至关重要。只 少量微生物需要突破粘膜表面才能引发疾病;然而， 已建立的Trm种群检测并迁移到新感染地区的机制 仍然未被探索。我们早期的工作，使用肠道细菌病原体耶尔森氏菌 假结核病（Yptb），确定了两个不同的CD 8 + Trm群体在肠道， 通过其整合素CD 103的表达来区分。CD 103 neg Trm细胞优先定位于 淋巴细胞簇在感染区域周围形成，限制病原体复制， 在感染消退后消散。CD 103阴性CD 4+和CD 8 + Trm群体也很丰富 在其他组织中，但它们各自在组织特异性免疫中的作用仍然知之甚少。 我们假设组织驻留淋巴细胞群体的多样性是功能性免疫应答的基础。 异质性，CD 103阴性淋巴细胞亚群能够局部迁移， 对组织特异性信号的反应，这些信号警告它们致病性损伤，并形成 二次攻毒期间，在新感染区域周围形成淋巴细胞簇。这些 研究将利用光转换来标记组织驻留细胞， 体内平衡和肠道感染期间的迁移。我们将利用这种技术来解决 我们对Trm生物学知识的根本差距包括：（1）Trm多样性如何与 二次感染期间的功能结果和（2）识别由 组织响应感染，驱动Trm动员和病原体控制。这些 实验有可能大大提高我们对组织驻留的理解， 淋巴细胞生物学以及如何定制免疫策略以改善Trm功能。